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PubMed2026

Machine Learning-Based Identification of Survival-Associated CpG Biomarkers in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an exceptionally aggressive cancer with a 5-year survival rate of less than 10%, driven by late-stage diagnosis, limited treatment options, and a lack of reliable biomarkers for early detection and prognosis. In this study, we integrated DNA methylation data from TCGA and ICGC cohorts, categorizing samples based on survival time, and identified 688 differentially methylated CpG sites, along with 224 CpG biomarkers significantly associated with patient survival through statistical and machine learning-based analyses. We developed a random forest model to predict patient survival, achieving 85.2% accuracy for short-survival patients and 70.0% for long-survival patients in the validation set. External dataset validation further confirmed the model's robustness and accuracy. De novo motif analysis of genomic regions surrounding the 224 CpG biomarkers identified TWIST1 and FOXA2 as key transcriptional regulators enriched in survival-associated CpG sites, linking their activity to patient survival outcomes. Collectively, our findings highlight valuable epigenetic biomarkers and provide a predictive model to assess PDAC risk levels post-surgery, offering the potential for improved patient stratification and personalized therapeutic strategies.

DNA methylation↗
PubMed2006

Enrolling research subjects from clinical practice: ethical and procedural issues in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial is a multi-site effectiveness study funded by the National Institute of Mental Health (NIMH) with the aim of identifying successful, acceptable and cost-effective treatment strategies for outpatients with unremitted depression. With enrollment of 4,041 adults with major depressive disorder (MDD), it is the largest controlled psychiatric treatment study ever undertaken. In the course of developing procedures to ensure that ambitious enrollment goals were met, a number of ethical and practical issues became apparent that underscore the conflicts between effectiveness research and human subject protections. These are delineated as they relate to study design; eligibility criteria; incentives to subjects; investigators and clinical sites; the complementary roles of clinical research coordinators (CRCs) and study clinicians; and recruitment and consent procedures. The STAR*D trial exemplifies the interplay and tension between those strategies that integrate research and clinical aims and roles in the service of enhancing external validity, site participation, and recruitment and retention versus those strategies that differentiate research and clinical treatment in the service of research integrity and human subject protections. We hope that a discussion of these key challenges and dilemmas and how they have been addressed will help inform future discussions concerning design and conduct of ethical effectiveness trials designed to optimize care in real world clinical settings.

Adolescent↗
PubMed2006

Remission in early psychosis: Rates, predictors, and clinical and functional outcome correlates.

BACKGROUND: Recently, the "Remission in Schizophrenia Working Group" proposed remission criteria consisting of a reduction to mild levels on key symptoms for at least 6 months. AIMS: This study applied these remission criteria to a large first-episode psychosis sample in order to (1) determine the rates of remission; (2) explore predictors of remission; and (3) test the external validity of these criteria. METHODS: We analyzed data from 462 subjects with a first-episode of psychosis who participated in a long-term, multinational, randomized, double-blinded trial of risperidone and haloperidol over 2 to 4 years. RESULTS: At some time point in the study 323 (70%) of the 462 subjects had a reduction to mild levels on the key symptoms as measured by the PANSS although only 109 (23.6%) maintained this level for at least 6 months thereby meeting remission criteria. The two strongest predictors of remission were shorter duration of untreated psychosis (p=0.01) and treatment response at 6 weeks (p=0.001). Compared to non-remitted patients, those in remission experienced greater improvement on all PANSS subscales (p<.0001), CGI-S (p<.0001), better quality of life (p=0.006), fewer relapses (p<.0001), displayed a more favorable attitude towards their medication (p=.002), had lower EPS levels according to the ESRS (p=<.0001) and received lower doses of antipsychotic medication (p=0.003). The remission and non-remission groups did not differ significantly regarding composite cognitive scores, suicidality and body mass index. CONCLUSIONS: The results suggest that the remission criteria, although based solely on core symptom improvement, can effectively identify patients who have a more favorable overall outcome.

Adolescent↗
PubMed2004

Use of near-infrared spectroscopy for determining the total arsenic content in prostrate amaranth.

The potential of near infrared spectroscopy (NIRS) for determining the total arsenic (As) content in the prostrate amaranth (Amaranthus blitoides S. Watson) was assessed. Seventy-four samples belonging to this species, were harvested at different maturity stages along the polluted area, and then were scanned by NIRS. Their As reference values were obtained by atomic absorption spectrometry and they were regressed against different spectral transformations using modified partial least square (MPLS) regression. First derivative transformation equation of the raw optical data, previously standardized by standard normal variate (SNV) and De-trending (DT) transformations, resulted in a coefficient of determination (r(2)) in the external validation of 0.63, indicative of equations that can be used for a correct separation of the samples into low, medium and high groups. The standard deviation to standard error of prediction ratio (RPD) and range to standard error of prediction ratio (RER) for the first derivative equation were similar to those obtained for other trace metal calibrations reported in NIRS reflectance. Major cell components such as chlorophyll, lipids, starch and proteins were used by MPLS for modeling the equations. The use of NIRS for the determination of the As content in A. blitoides plants offers an important saving of time and cost of analysis.

Amaranthus↗
PubMed2004

Correlation between rating scales and sleep laboratory measurements in restless legs syndrome.

OBJECTIVES: The aim of this study was to test the external validity of the International Restless Legs Scale (IRLS) by assessment of the correlation between IRLS scores and objective measures of severity such as polysomnography (PSG) and Suggested Immobilization Test (SIT). DESIGNS: Correlation analysis between rating scales for RLS (IRLS and Johns Hopkins RLS Scale--JHRLSS) and sleep laboratory measurements in untreated RLS patients. METHODS: The study included 30 untreated patients diagnosed with RLS according to the criteria of the International RLS Study Group. Diagnostic procedures included physical exam, laboratory analysis, PSG and a nocturnal SIT. Statistical analysis was performed by means of Spearman's correlations and Kruskal-Wallis test. RESULTS: IRLS correlated significantly with Periodic Leg Movement of Sleep-index (PLMS), and PLMS-arousal index during PSG as well as with Periodic Leg Movement of Wakefulness (PLMW) during SIT (SIT-PLMW) (all r=0.4; p<0.01). There was no correlation between IRLS and the number of PLMW in PSG (PSG-PLMW) or any other sleep variable during PSG. Nor was any correlation found between IRLS scores and ferritin, age, duration of illness or any other clinical variables. CONCLUSIONS: This study represents the first demonstration of a correlation between IRLS and objective parameters of motor dysfunction such as PLMS-index or SIT. This finding is particularly relevant for the design of future clinical trials. Furthermore, the association between PLMS and SIT-PLMW supports the view that both PLMS and PLMW might share a common mechanism.

Adult↗
PubMed2006

Mixture models of serum iron measures in population screening for hemochromatosis and iron overload.

Homozygosity for the C282Y mutation of the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. The authors describe and apply methodology developed for the analysis of phenotypic and genotypic data from 46,136 non-Hispanic Caucasians, a subset of the multi-ethnic cohort enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. For analysis of the distribution of transferrin saturation (TS), mixtures of normal distributions were considered and the expectation-maximization (EM) algorithm was applied for parameter estimation. Maximized log-likelihoods were compared, and significance was assessed by resampling. Sensitivity, specificity, and predictive values from the modeled subpopulations were compared with the actual observed genotypes for C282Y and H63D mutations in the HFE gene. A strong association between HFE genotype and TS subpopulations was found in these data collected from different geographic regions, confirming the external validity of the statistical approach when applied to population-based data. It was concluded that mixture modeling of phenotypic data may provide a clinical guide for screening with gender-specific thresholds to identify potential samples for genetic testing.

Adult↗
PubMed2006

Reliability of language mapping with magnetic source imaging in epilepsy surgery candidates.

The external validity of a noninvasive language mapping protocol with magnetoencephalography (MEG) has been established through direct comparisons with invasive functional mapping techniques. This study examines the test-retest and interrater reliability of this protocol under realistic testing conditions in 21 epilepsy surgery candidates. Brain activation maps were obtained in the context of an auditory word recognition task and represented by temporally contiguous dipolar activity sources. Both the duration and strength of the associated magnetic flux were used as measures of the magnitude of regional brain activity. Hemispheric asymmetry indices based on these measures showed good interrater reliability and intraparticipant reproducibility. Similar findings were obtained with respect to the location of the geometric center of receptive language-specific cortex (Wernicke's) area in the dominant hemisphere. The results further support the adequacy of this MEG-based brain mapping protocol as a noninvasive tool for receptive language localization in epilepsy surgery candidates.

Adolescent↗
PubMed2004

Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose.

Estimating the maximum recommended starting dose (MRSD) of a pharmaceutical for phase I human clinical trials and the no observed effect level (NOEL) for non-pharmaceuticals is currently based exclusively on an extrapolation of the results of animal toxicity studies. This process is inexact and requires the results of toxicity studies in multiple species (rat, dog, and monkey) to identify the no observed adverse effect level (NOAEL) and most sensitive test species. Multiple uncertainty (safety) factors are also necessary to compensate for incompatibility and uncertainty underlying the extrapolation of animal toxicity to humans. The maximum recommended daily dose for pharmaceuticals (MRDD) is empirically derived from human clinical trials. The MRDD is an estimated upper dose limit beyond which a drug's efficacy is not increased and/or undesirable adverse effects begin to outweigh beneficial effects. The MRDD is essentially equivalent to the NOAEL in humans, a dose beyond which adverse (toxicological) or undesirable pharmacological effects are observed. The NOAEL in test animals is currently used to estimate the safe starting dose in human clinical trials. MDL QSAR predictive modeling of the human MRDD may provide a better, simpler and more relevant estimation of the MRSD for pharmaceuticals and the toxic dose threshold of chemicals in humans than current animal extrapolation based risk assessment models and may be a useful addition to current methods. A database of the MRDD for over 1300 pharmaceuticals was compiled and modeled using MDL QSAR software and E-state and connectivity topological descriptors. MDL QSAR MRDD models were found to have good predictive performance with 74-78% of predicted MRDD values for 120 internal and 160 external validation compounds falling within a range of +/-10-fold the actual MRDD value. The predicted MRDD can be used to estimate the MRSD for pharmaceuticals in phase I clinical trials with the addition of a 10-fold safety factor. For non-pharmaceutical chemicals any compound-related effect can be considered an undesirable and adverse toxicological effect and the predicted MRDD can be used to estimate the NOEL with the addition of an appropriate safety factor.

Animals↗
PubMed2005

In silico screening of chemicals for bacterial mutagenicity using electrotopological E-state indices and MDL QSAR software.

Quantitative structure-activity relationship (QSAR) software offers a rapid, cost effective means of prioritizing the mutagenic potential of chemicals. MDL QSAR models were developed using atom-type E-state indices and non-parametric discriminant analysis. Models were developed for Salmonella typhimurium gene mutation, combining results from strains TA97, TA98, TA100, TA1535, TA1536, TA1537, and TA1538 (n=3228), and Escherichia coli gene mutation tests WP2, WP100, and polA (n=472). Composite microbial mutation models (n=3338) were developed combining all Salmonella, E. coli, and the Bacillus subtilis rec spot test study results. The datasets contained 74% non-pharmaceuticals and 26% pharmaceuticals. Salmonella and microbial mutagenesis external validation studies included a total of 1444 and 1485 compounds, respectively. The average specificity, sensitivity, positive predictivity, concordance, and coverage of Salmonella models was 76, 81, 73, 78, and 98%, respectively, with similar performance for the microbial mutagenesis models. MDL QSAR and discriminant analysis provides rapid and highly automated mutagenicity screening software with good specificity, sensitivity, and coverage that is simpler and requires less user intervention than other similar software. MDL QSAR modules for microbial mutagenicity can provide efficient and cost effective large scale screening of compounds for mutagenic potential for the chemical and pharmaceutical industry.

Algorithms↗
PubMed2001

Area-wide urban traffic calming schemes: a meta-analysis of safety effects.

This paper presents a meta-analysis of 33 studies that have evaluated the effects on road safety of area-wide urban traffic calming schemes. Area-wide urban traffic calming schemes are typically implemented in residential areas in towns in order to reduce the environmental and safety problems caused by road traffic. A hierarchical road system is established and through traffic is removed from residential streets by means of, for example, street closures or one-way systems. Speed reducing devices are often installed in residential streets. Main roads are improved in order to carry a larger traffic volume without additional delays or more accidents. The meta-analysis shows that area-wide urban traffic calming schemes on the average reduce the number of injury accidents by about 15%. The largest reduction in the number of accidents is found for residential streets (about 25%), a somewhat smaller reduction is found for main roads (about 10%). Similar reductions are found in the number of property damage only accidents. The results of evaluation studies are robust with respect to study design. There is no evidence of publication bias in evaluation studies. Study findings are found to have high external validity.

Accidents, Traffic↗
PubMed1995

Rehabilitation teams decisions on discharge housing for stroke patients.

For older people who have had a stroke, appropriate housing can promote independence and well being. However, suboptimal team accommodation recommendations may result in placement of an individual where their needs are not met, and their skills are not maximized. Although clinical judgments regarding patient discharge are routinely made by rehabilitation teams, this area has received limited research attention. This study examines how rehabilitation teams determine the most appropriate housing to recommend to stroke patients after their discharge from hospitals. A Social Judgment Theory approach was used to document and analyze the accommodation recommendations and policies of 13 rehabilitation teams (clinician n = 74). Teams were asked to consider 50 hypothetical stroke patients, and determine the most appropriate discharge housing to recommend to these patients. Each stroke patient was described in terms of 8 attributes: mobility status, ability to manage their own affairs, patient's choice of housing, personal activity of daily living (ADL) skills, domestic and community ADL skills, general health status, social situation, and premorbid living arrangements. Clinicians were provided with a response scale on which to record their recommendations. The results showed considerable yet reliable differences among teams concerning recommendations made, and judgment policies adopted. Although the highly structured and hypothetical nature of this research limits the external validity of findings, the results suggest that teams may also face difficulties with housing recommendations in the more complex clinical environment. Further studies to assess actual clinical team decision making are needed. Such studies could lead to the development of a standardized research-based protocol to help teams formalize and optimize their housing recommendations.

Aged↗
PubMed1998

Seat interface pressures of individuals with paraplegia: influence of dynamic wheelchair locomotion compared with static seated measurements.

OBJECTIVE: To provide a comparison of the seat interface pressures between static seating and dynamic seating during wheelchair locomotion of individuals with paraplegia. DESIGN: Repeated measures multivariate analysis of variance (MANOVA) comparing two conditions: static seat and dynamic seat interface pressures. SETTING: University campus and clinic. PARTICIPANTS: Fifteen participants, each of whom propelled a manual wheelchair for at least 5 hours per week over the previous 6 months and functioned with a spinal cord injury/ disability level of T1 or below. MAIN OUTCOME MEASURES: Peak pressure (PP) and pressure time integral (PTI) as measured by the Novel Pliance System, which consists of a flexible 32 x 32 capacitive sensor mat (each sensor 1.5 cm2) interfaced with a PC, was sampled at 10Hz. The participants were measured in their own wheelchair with a new Jay Active seat cushion. RESULTS: The repeated measures MANOVA showed a difference in the PP and PTI between the static and dynamic measurements (Wilk's = .00, p < .05). Follow-up dependent t tests yielded a difference in PP (t = 5.40, p < 0.025) and no difference in the PTI between static and dynamic conditions (t = 1.45, p > 0.025). The PP during static seating (mean = 16.2 +/- 5.0 kPa [121 +/- 37.5 mmHg]) was less than during dynamic seat interface pressures during wheelchair locomotion (20.03 +/- 6.6 kPa [152.3 +/- 49.5 mmHg]). PP varied by up to 42% during the wheelchair locomotion cycle. The PTI was similar between static (30.1 +/- 9.3 kPa [225.75 +/- 69 mmHg]) and dynamic conditions (36.2 +/- 18.1 kPa [271 +/- 135.7 mmHg]). CONCLUSIONS: The results from this study are consistent with some of the previous work on the nondisabled and a single case study, but with greater external validity because of the nature of the sample chosen and the methodology employed. PPs were greater during dynamic wheelchair locomotion compared with static seating interface pressures, with the peak varying up to 42% during the wheelchair locomotion cycle. The PTI indicates that the cumulative effect of the loading was comparable between conditions. The question that remains is whether this dynamic loading, resulting in a change in PP throughout the cycle, has a significant effect on tissue health.

Adult↗
PubMed1996

A systematic replication of the prescriptive treatment of school refusal behavior in a single subject.

We employed a multiple-baseline design to test the efficacy of a recently developed approach for reducing school refusal behavior. This approach uses a systematic method for conducting a functional analysis for the target behaviors and suggests specific intervention strategies based upon this analysis. To maximize external validity, the intervention was tested using a systematic replication strategy, whereby only the major conceptual elements of the intervention were retained from previous applications. The subject was a 10 year old girl who attended school with great difficulty and resistance and who was assigned DSM-III-R diagnoses of separation anxiety disorder and social phobia prior to treatment. Following 8 weeks of treatment, she showed marked reductions in problem behavior and no longer met criteria for any anxiety disorder diagnoses. The results highlight the importance of the use of functional analytic strategies to effect behavior change.

Anxiety, Separation↗
PubMed2001

Graded exposure in vivo in the treatment of pain-related fear: a replicated single-case experimental design in four patients with chronic low back pain.

The aim of this investigation was to examine the effectiveness of a graded exposure in vivo treatment with behavioural experiments as compared to usual graded activity in reducing pain-related fears, catastrophising and pain disability in chronic low back pain patients reporting substantial fear of movement/(re)injury. Included in the study were four consecutive CLBP patients who were referred for outpatient behavioural rehabilitation, and who reported substantial fear of movement/(re)injury (Tampa Scale for Kinesiophobia score>40). A replicated single-case cross-over design was used. After a no-treatment baseline measurement period, the patients were randomly assigned to one of two interventions. In intervention A, patients received the exposure first, followed by graded activity. In intervention B, the sequence of treatment modules was reversed. Sixty-three daily measures of pain-related cognitions and fears were recorded with visual analogue scales. Before and after the treatment, the following measures were taken: pain-related fear, pain catastrophising, pain control and pain disability. Using time series analysis on the daily measures of pain-related cognitions and fears, we found that improvements only occurred during the graded exposure in vivo, and not during the graded activity, irrespective of the treatment order. Analysis of the pre-post treatment differences also revealed that decreases in pain-related fear concurred with decreases in pain catastrophising and pain disability, and in half of the cases an increase in pain control. This study shows that the external validity of exposure in vivo also extends to the subgroup of chronic low back pain patients who report substantial fear of movement/(re)injury.

Accidents, Occupational↗
PubMed2003

Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD).

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age >/= 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, the treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention.

Bipolar Disorder↗
PubMed1997

Studies of violent and nonviolent male parolees: I. Laboratory and psychometric measurements of aggression.

Male parolees were recruited into a laboratory study to determine the relationship between their previous aggression history, psychometric measures of aggression, and behavioral measures of aggressive responding using a laboratory methodology: the Point Subtraction Aggression Paradigm. Subjects were assigned to a violent or nonviolent group based upon their criminal history. Subjects participated in sessions in which they were given three response options defined as: (1) nonaggressive responding which earned money, (2) aggressive responding which ostensibly subtracted money from another fictitious person, (This responding was defined as aggressive since it resulted in the ostensible delivery of an aversive stimulus (subtraction of money) to another person), and (3) escape which protected the subject's earnings from subtractions initiated by the other person. Results indicated that the violent subjects emitted significantly more aggressive responses than subjects in the nonviolent group. The number of aggressive responses parolees emitted was significantly correlated with most psychometric measures of aggression. This study provides external validity for our laboratory measurement of human aggressive responding, since aggressive responding was directly related to violent criminal histories.

Adult↗
PubMedDate not supplied

Comorbidity of panic and somatization disorder: a genetic-epidemiological approach.

Although recent diagnostic systems support the distinctiveness of panic disorder (PD) and somatization disorder, a high level of comorbidity of these two diagnoses has been reported, indicating a need for investigations with external validators. One hundred fifty-nine outpatients with DSM-III-R PD and 76 surgical controls were screened for lifetime presence of DSM-III-R somatization disorder, and the risks for some types of psychiatric disorders in their families were computed. In our sample, 23% of women and 5% of men with PD also had DSM-III-R somatization disorder did not differ from women with PD only in age at onset of panic, agoraphobia, childhood history of separation anxiety, or lifetime diagnoses of other disorders. Familial risks for PD, PD-agoraphobia, and alcohol dependence were significantly higher for families of women with PD and women with PD plus somatization disorder than for controls. The familial risks for antisocial personality (ASP) disorder (a familial indicator for the somatization disorder spectrum of liability, phenomenologically independent from both PD and somatization disorder) were significantly higher for families of women with PD plus somatization disorder than for families of women with PD only or for controls. Application of DSM-IV criteria for somatization disorder substantially decreased the comorbidity with PD. Our data suggest that somatization disorder is not simply a form of PD, and that the two disorders may coexist in the same subject without sharing a common genetic diathesis. Compared with DSM-III-R, DSM-IV criteria for somatization disorder appear to be simpler in structure and of less complicated application.

Adult↗
PubMedDate not supplied

An investigation of the Self-Report Manic Inventory as a diagnostic and severity scale for mania.

The initial study on the Self-Report Manic Inventory (SRMI) reported that it reliably diagnosed mania. In the current study, we replicated the initial study on the SRMI. We also evaluated its ability to quantify manic symptomatology and to measure change during inpatient treatment. The findings show that manic patients are capable of reporting their symptoms, regardless of their insight into their condition. They also confirm that the SRMI is a reliable diagnostic instrument and that it performs consistently over time when used with a 1-week time format. The SRMI is also sensitive to clinical improvement in hospitalized patients undergoing treatment. The SRMI correlated well with the Young Mania-Rating Scale (YMRS), which served as an external validator of SRMI scores at the beginning and end of hospitalization. Factor analysis produced two groups of manic subjects who closely resemble the hedonistic euphoric type and the energized dysphoric type initially reported by Shugar et al.

Adult↗